γ-Secretase-dependent processes in microglial function
γ-Secretase and microglia
Missense mutations in the two presenilin (PS) genes are a major cause of early onset familial Alzheimer's disease (AD). PS proteins assemble with other proteins to form the γ-secretase complex that mediates cleavage of the β-amyloid precursor protein (βAPP) resulting in the generation of the amyloid β-peptide (Aβ). Beside βAPP, γ-secretase also cleaves a number of additional type I membrane proteins. Consistent with cleavage of multiple protein substrates, γ-secretase is involved in the trafficking and intracellular signaling of distinct proteins, thereby affecting several pathways in cellular metabolism and differentiation. PS/γâˆ’secretase also regulates the endocytosis of select membrane proteins. However, the underlying molecular mechanisms and the physiological relevance remain largely unknown. The proposed project aims to elucidate the role of PS/γâˆ’secretase in microglial functions, including activation, migration, and phagocytosis. We will use pharmacological and molecular biological approaches to interfere with microglial γ-secretase activity and analyze the effects on these processes. Moreover, the role of familial AD associated mutations in microglial function will be assessed. Of particular interest will be the role of γ-secretase in the endocytosis and metabolism of Aβ. To characterize the underlying molecular mechanisms, the endocytosis of specific receptors for Aβ will be analyzed and microglial γ-secretase protein substrates be identified. In order to verify the data obtained by cell culture experiments, we will generate and analyze a mouse model with impaired γ-secretase function in microglia. Together, the proposed project should give insight into physiological and pathophysiological functions of AD associated PS proteins in microglia.